PATHOLOGY IN THE CONTROL OF DIFFERENTIATION IN CANCER

五年前，在这项赠款的开始，我们提出了 综合控制缺陷表达假说 细胞分化和增殖的作用 致癌作用。 为了验证这一假设，我们首先启动了 研究如何建立分化的综合控制 正常细胞的增殖受到调节 调解这些进程。 我们接下来进行了实验， 确定是否以及如何诱导致癌作用， 化学和/或物理制剂取消了综合防治 细胞的分化和增殖。 出色进展 在所有这些研究中，|我们确定， 介导分化和增殖的综合控制 在一个独特的细胞周期停滞状态下， 生物学事件必须作为这种调节的一部分发生， 机制，这一监管过程是显而易见的，无论是在 小鼠间充质干细胞和正常人表皮 细胞 此外，我们还在以下方面取得了重大进展： 鉴定和纯化生理调节分子， 控制这些过程的人类血液。 我们还建立 引发致癌作用的物理和化学物质， 因为完全的致癌作用可以诱导稳定的缺陷， 细胞分化和增殖的综合控制 间充质干细胞和初步结果表明， 在正常人表皮细胞中发生类似的事件。 我们 因此，现在建议扩大这些研究， 目标是建立管理综合 控制细胞分化和增殖， 致癌物质破坏这些关键的机制， 监管程序。

Five years ago at the inception of this grant, we presented the hypothesis that the expression of defects in the integrated control of cellular differentiation and proliferation served a significant role in carcinogensis. To test this hypothesis we first initiated studies to establish how the integrated control of differentiation and proliferation is regulated in normal cells and what events mediate these processes. We next performed experiments to determine if and how the induction of carcinogenesis with chemical and/or physical agents abrogates the integrated control of cellular differentiation and proliferation. Excellent progress has been made in all these studies| We established that the integrated control of differentiation and proliferation is mediated at a distinct cell cycle arrest state, that a specific sequence of biological events must occur as part of this regulatory mechanism, and that this regulatory process is evident both in murine mesenchymal stem cells and in normal human epidermal cells. In addition, we have made significant progress in identifying and purifying physiological regulatory molecules from human blood that control these processes. We also established that physical and chemical agents that initiate carcinogenesis or cause complete carcinogenesis can induce stable defects in the integrated control of cellular differentiation and proliferation in mesenchymal stem cells and preliminary results suggest that comparable events occur in normal human epidermal cells. We therefore now propose to expand these studies with the specific goal to establish the mechanisms that regulate the integrated control of cellular differentiation and proliferation and the mechanisms by which carcinogenic agents disrupt these critical regulatory processes.